Abstract Lipid traits are known to be sex-differential, but the underlying molecular players are largely unknown. Herein, we aim to highlight differential molecular signatures in lipid metabolism between males and females by identifying proteins that are causally linked to lipids in a sex-specific or sex-differentiated manner. Since protein levels are downstream products of gene expression, proteomics data can be crucial to understand etiology of sex-differences in lipids metabolism. We used sex-specific pQTL summary statistics for 2,923 circulating proteins measured in the UK Biobank Pharma Proteomics Project, along with sex-specific summary statistics of lipids from the Global Lipids Genetics Consortium. We combined these using two-sample Mendelian Randomization analyses and applied stringent multiple testing p-values correction and sensitivity analyses. We identified several sex-specific significant causal links between protein levels and lipid phenotypes: 83 were exclusive to females and 82 to males, 46% of which would not have been identified using combined-sex GWASs. The estimated causal effect was instead significant in both sexes but substantially different in size for 39 causal relationships (p < 0.05). Intriguingly, several of these proteins were previously shown to be involved in inflammation and cardiometabolic diseases, such as Apolipoprotein(a) and lipoprotein lipase. Furthermore, two sex-specific proteins — LEPR and LPA — are molecular targets of emerging cardiometabolic therapies, highlighting the need for future investigations to determine whether these protein-level differences translate into sex-specific efficacy or safety in clinical trials and routine treatments. The discovery of these sex-differences can provide important etiological insights into the management of lipid metabolism. Such knowledge may in turn improve the predictive use of sex-specific pQTLs and point to new therapeutic gender specific strategies to prevent cardiovascular disease.

BACKGROUND:Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. OBJECTIVE:To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. DESIGN:We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. RESULTS:Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. CONCLUSIONS:This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.

Sex differences in the gut microbiome are well established, yet the contribution of reproductive hormone variations within women remains insufficiently characterized. Here, we investigated how hormonal fluctuations during a natural menstrual cycle shape gut microbiome in healthy women and whether these effects are distinct from dietary influences. Leveraging longitudinal shot-gun gut microbiome data from 160 Italian participants in the Women4Health cohort, combined with detailed dietary information, we examined relationships with five reproductive hormones hormones: 17β-estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin. Microbial alpha diversity was significantly lower at the follicular phase compared to ovulatory phase (p = 0.03), while beta diversity significantly increased from follicular to the late luteal phase (p = 8.7x10 − 6 ). Twenty-eight species and twenty-two microbial pathways were significantly associated with reproductive hormones, with the majority of associations observed for gonadotropins (FSH and LH) rather than gonadal steroids (17β-estradiol and progesterone). While we confirm strong relationships between diet and microbiome, mediation analysis showed no evidence for a mediating effect of hormones on those. Together, these findings reveal distinct hormonal and dietary influences on gut microbiome across the menstrual cycle in healthy women.

BACKGROUND:Genetic studies of stool frequency (SF), an indirect proxy for gastrointestinal transit, may reveal therapeutically tractable pathways relevant to IBS and other dysmotility disorders. OBJECTIVE:To identify genes and mechanisms involved in gut motility, providing a foundation for clinical translation. DESIGN:We performed a multiancestry genome-wide association study (GWAS) meta-analysis of SF in 268 606 European and East Asian individuals. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS signals were fine-mapped and functionally annotated to prioritise candidate genes and pathways. Findings implicating thiamine metabolism were followed-up with dietary interaction analyses in UK Biobank (UKB). RESULTS:SF heritability was comparable in Europeans (7.0%) and East Asians (5.6%). We observed strong genetic correlations with gastrointestinal and psychiatric disorders (rg=0.18-0.47), and causal effects on IBS. Novel correlations with cardiovascular traits (rg=0.12-0.14) were supported by drug signature enrichment analyses. We identified 21 independent loci, including 10 novel signals implicating bile acid synthesis (KLB) and cholinergic signalling (COLQ). Fine-mapping converged on vitamin B1 metabolism, highlighting single-variant causal effects at SLC35F3 (a thiamine transporter) and XPR1 (phosphate exporter essential for thiamine activation). In 98 449 UKB participants, thiamine intake was positively associated with SF (p<0.0001), and a combined SLC35F3/XPR1 genotype score significantly modulated this effect (p<0.0001). CONCLUSIONS:We identify therapeutically tractable mechanisms involved in the control of gut motility, including a previously unrecognised role for vitamin B1. These findings warrant mechanistic and clinical studies to evaluate their translational potential in IBS and other dysmotility syndromes.

Menopause is a hallmark of women's aging and is frequently portrayed as a medical issue. It also encompasses social and biological aspects often neglected and not well-understood, leaving women with insufficient support and attention. With the decline in estrogen levels, starting years before menopause is fully established, women experience various physical symptoms, and the risk of many age-related diseases increases sharply soon after these hormonal changes occur. Notably, these hormonal shifts also significantly impact the vaginal and gut microbiomes, contributing to dysbiosis and influencing the onset and progression of several diseases. Here, we examined the complex and dynamic relationship among aging, menopause, and microbiome changes with a particular focus on the vaginal and gut ecosystems. Emerging research highlights diet as a potential modulator for maintaining microbiome health during menopause. A deeper understanding of microbiome changes across life stages suggests the potential for microbiome-targeted strategies to support well-aging in women.

Large sex hormonal fluctuations are thought to influence vaginal microbiota, but little is known about the impact of small, physiological variations. Here we tracked changes in vaginal microbiota during four key menstrual cycle phases in 61 healthy Italian women from the Women4Health cohort. The microbiota was primarily composed of Lactobacillus, with L. iners being the most abundant. Noteworthy, the high abundance of L. iners contrasts with previous studies in European populations, challenging its proposed pathogenic role, and suggesting distinct microbiota profiles within Europe. Individual microbiotas were generally stable, but beta diversity was higher during the follicular phase. Only 11 women exhibited compositional shifts and those mostly occurred between follicular and ovulatory phases. Finally, among the hormones evaluated, 17-beta estradiol had the largest impact on taxa abundance variations. Our study highlights specific features of the Italian population and points to the resilience of the vaginal microbiota to physiological hormonal changes. ### Competing Interest Statement The authors have declared no competing interest.

In the past 20 years, the involvement of gut microbiome in human health has received particular attention, but its contribution to age-related diseases remains unclear. To address this, we performed a comprehensive two-sample Mendelian Randomization investigation, testing 55130 potential causal relationships between 37 traits representing gut microbiome composition and function and age-related phenotypes, including 1472 inflammatory and cardiometabolic circulating plasma proteins from UK Biobank Pharma Proteomic Project and 18 complex traits. A total of 91 causal relationships remained significant after multiple testing correction (false discovery rate p-value <0.05) and sensitivity analyses, notably two with the risk of developing age-related macular degeneration and 89 with plasma proteins. The link between purine nucleotides degradation II aerobic pathway and apolipoprotein M was further replicated using independent genome-wide association study data. Finally, by taking advantage of previously reported biological function of Faecalibacterium prausnitzii we found evidence of regulation of six proteins by its function as mucosal-A antigen utilization. These results support the role of gut microbiome as modulator of the inflammatory and cardiometabolic circuits, that may contribute to the onset of age-related diseases, albeit future studies are needed to investigate the underlying biological mechanisms.

AIMS:Endometriosis (EM) is a chronic inflammatory disorder with multifactorial etiologies (i.e., genetics and environmental factors, hormonal and immunological changes, and microbiome alterations). The complement system is one of the most frequently dysregulated pathways in EM. Mannose-binding lectin (MBL), a carbohydrate pattern recognition molecule, is the first described recognition subcomponent of the complement lectin pathway (LP). Here, we unveiled the interplay among MBL polymorphisms, plasma levels, LP functionality, and microbiota as potential contributors to EM pathogenesis. MATERIALS AND METHODS:A cohort of 38 EM patients and 20 healthy controls was enrolled, and the levels and functionality of the LP were assessed via ELISA. MBL genetic variants and the endometrial and vaginal microbiome were investigated and correlated. KEY FINDINGS:High MBL levels were related to the disease severity, although not accountable for the MBL2 genotype. MBL and MASP-2 were present in the uterine mucosa but appeared to have no activity at the endometriotic lesion. EM patients with LP functional deficit displayed pathogenic bacterial species more frequently in the endometrial microbiome. Moreover, women affected by EM showed a higher frequency of rare gene variants in the estrogen pathway genes, potentially affecting MBL plasma levels. SIGNIFICANCE:A lower functionality of LP in the uterine mucosa may contribute to an unbalanced bacterial environment that could activate endometrial cells. Not only the genotype and the inflammatory condition, but also the estrogen pathway can cause altered MBL levels, thus contributing to changes in the LP functionality.

In the past 20 years, the involvement of gut microbiome in human health has received particular attention, but its contribution to age-related diseases remains unclear. To address this, we performed a comprehensive investigation of 4,033 potential causal relationships between 37 traits representing gut microbiome composition and function and 109 age-related phenotypes, using two-samples Mendelian randomization. Five causal relationships remained significant after multiple testing correction and sensitivity analyses, specifically between two taxa of Coriobacteriales and the risk of developing age-related macular degeneration, species Bifidobacterium adolescentis and levels of TNFSF12 protein in plasma, and the lactose-galactose degradation microbial I pathway and levels of IL-15Rα and TRAIL proteins in plasma. The causal relationship between the lactose-galactose degradation I pathway and TRAIL protein levels was further confirmed using independent data. These results support the role of gut microbiome in regulating the inflammatory circuit, albeit future studies are needed to investigate the underlying biological mechanisms. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by project DSB AD006.371 "InvAt" FOE 2022 and project DBA.AD005.225 "NutrAGE" FOE 2021. In addition, we acknowledge Marie-Curie Fellowship to D.Z., acronym "Sex Dimorphism" (GA n. 101066678) that indirectly made this study possible. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes No data was generated for this study. We used public data, download links are available in Supplementary Table 1. The scripts used for all the analyses are publicly available in the GitHub repository: https://github.com/Sanna-s-LAB/Mendelian-randomization-Project.git

BACKGROUND & AIMS:Irritable bowel syndrome (IBS) shows genetic predisposition, and large-scale genome-wide association studies (GWAS) are emerging, based on heterogeneous disease definitions. We investigated the genetic architecture of IBS defined according to gold standard Rome Criteria. METHODS:We conducted GWAS meta-analyses of Rome III IBS and its subtypes in 24,735 IBS cases and 77,149 asymptomatic control subjects from 2 independent European cohorts (UK Biobank and Lifelines). Single-nucleotide polymorphism (SNP)-based heritability (h2SNP) and genetic correlations (rg) with other traits were calculated. IBS risk loci were functionally annotated to identify candidate genes. Sensitivity and conditional analyses were conducted to assess impact of confounders. Polygenic risk scores were computed and tested in independent datasets. RESULTS:Rome III IBS showed significant SNP-heritability (up to 13%) and similar genetic architecture across subtypes, including those with manifestations at the opposite ends of the symptom spectrum (rg = 0.48 between IBS-D and IBS-C). Genetic correlations with other traits highlighted commonalities with family history of heart disease and hypertension, coronary artery disease, and angina pectoris (rg = 0.20-0.45), among others. Four independent GWAS signals (P < 5×10-8) were detected, including 2 novel loci for IBS (rs2035380) and IBS-mixed (rs2048419) that had been previously associated with hypertension and coronary artery disease. Functional annotation of GWAS risk loci revealed genes implicated in circadian rhythm (BMAL1), intestinal barrier (CLDN23), immunomodulation (MFHAS1), and the cyclic adenosine monophosphate pathway (ADCY2). Polygenic risk scores allowed the identification of individuals at increased risk of IBS (odds ratio, 1.34; P = 1.1×10-3). CONCLUSIONS:Rome III Criteria capture higher SNP-heritability than previously estimated for IBS. The identified link between IBS and cardiovascular traits may contribute to the delineation of alternative therapeutic strategies, warranting further investigation.

The importance of the gut microbiome in human health has been widely recognized, with alterations in species abundances now reported for many different diseases. In recent years, observations of within-species genetic diversity and strain-level functional differences have urged the field to transition to analyzing microbes at the genetic level, taking advantage of genetic variants in the metagenome to pinpoint relevant genes and pathways. Here, we conducted a phenome-wide association study (PheWAS) of 12.7 million gut microbial single nucleotide variants (SNVs) with 244 host health phenotypes and environmental exposures in 10,781 individuals from six independent cohorts from Europe and Africa. We found 3,018 associations supported by at least two cohorts for 105 host factors, including age, sex and cardiovascular and metabolic parameters. Moreover, we found 34,927 significant associations in single-cohort analyses where SNV–phenotype pairs were only available for one cohort. All identified associations are detailed in an online catalog (https://fulab.web.rug.nl/SNV-MWAS/). The associated microbial SNVs inform mechanistic hypotheses about microbial functionality in human health and provide insights into microbial adaptation and evolution in response to changes in the environment and host physiology. For example, we identified 718 age-associated gut microbial SNVs across multiple cohorts and used these microbial SNVs to accurately predict host age. We also identified SNVs in microbial genes associated with lipid concentrations and BMI, including SNVs in the isoleucine-tRNA synthetase gene of Clostridium phoceensis and an α-Melanocyte-stimulating hormone-mimicking clpB gene of Alistipes ihumii. Mediation analysis provided evidence that microbial genetic variations may be under selection enforced by environmental factors, but also that they mediate the effects on the host, e.g. the isoleucyl-tRNA synthetase gene of C. phoceensis mediated dietary effects on four phenotypes. Overall, this study identifies new biological connections between human host and microbial genetic variants, exposing the functional layer of gut microbiome data hidden at base pair resolution and revealing microbial adaptation and evolution in relation to host lifestyle and physiology.

Primary open -angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta -analysis across 15 biobanks (of the Global Biobank Meta -analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multiancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene -enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of SIX6 and CDKN2B-AS1 loci in human GTEx data and across large electronic health records showing interaction between SIX6 gene and causal variants in the chr9p21.3 locus, with expression effect on CDKN2A/B. Our results suggest that some POAG risk variants may be ancestry specific, sex specific, or both, and support the contribution of genes involved in programmed cell death in POAG pathogenesis.

Recently in Gut, Zhu and colleagues investigated causality of genetic risk effects across three genetically correlated conditions: haemorrhoidal disease (HEM), diverticular disease (DIV) and IBS. Using genomewide association study (GWAS) summary statistics from our previous HEM GWAS and other studies, they conducted unidirectional twosample Mendelian randomisation (MR) and concluded ‘HEM might not be a trigger for developing diverticular disease or IBS, providing novel insights into a modest genetic correlation in conditions. Simultaneously, the observed causal (protective, ed.) effects of HEM on diverticular disease and IBS requires further exploration’. Although we did not originally make any claims of causality from the observed genetic correlations, the findings of Zhu et al are surprising and not in line with previous results, hence we set out to investigate further the relationship between HEM, DIV and IBS. Here, we briefly report an analysis that differs from Zhu et al in that: (1) we used best practice twosample MR analysis, (2) causality was studied bidirectionally (testing HEM both as exposure (cause) and outcome (effect) versus DIV and IBS risk) and (3) summary statistics from the largest, recent GWAS metaanalysis including >53 000 IBS cases were used to test genetic risk effects of HEM relative to IBS (online supplemental material). By these means, we obtained results different from Zhu et al and new evidence of causative effects of DIV and (to a lesser extent) IBS towards the risk of HEM. Figure 1, online supplemental figure S1 and S2 illustrate the outcome of our analyses, outlined below. We first optimised the instrument variable (IV) selection for MR by using consensus thresholds and methods to select genetic variants that are: associated with the exposure (p<5×10 or p<5×10); not in linkage disequilibrium (LD) (r<0.001 across a 1 Mb window); and not horizontally pleiotropic (having no direct association with the outcome) (pMRPRESSO<0.05). Then, using the selected variants as IVs, we performed bidirectional twosample MR analyses 9 using inverse variance weighted (IVW), MR Egger, weighted median, simple mode, weighted mode and CAUSE methods. Additionally, to ensure the robustness of the causal effects, we performed leaveoneout IVW regression analysis, which shows that causal effects are not driven by a few outlying genetic variants (online supplemental material). Hence, this pipeline was first applied to testing HEM as exposure towards the risk of developing DIV or IBS (outcome) as in Zhu et al. In contrast to Zhu et al, no significant findings were obtained in our analysis in this direction (see HEM exposure in figure 1). However, when either DIV or IBS were tested as exposure on HEM as outcome, significant observations were made using multiple MR models (see HEM outcome in figure 1). In particular, MR based on the IVW method resulted in strongest and most significant findings, both for IBS and for DIV showing predisposing effects on HEM. Remarkably, DIV was associated with nearly five times increased HEM risk (OR=4.8; p=2×10). While their results were limited to testing HEM as exposure, discrepancies with Zhu et al are most likely due to the fact that they used IVs variants that are in LD and therefore not independent (as required for MR analyses; a detailed analysis of methodological issues is reported in the online supplemental material). In summary, we show that DIV and IBS significantly predispose to HEM. This is in line with realworld data, as a most recent colonoscopy study also demonstrated: not only were patients with DIV more likely to have internal HEM (OR=2.21) but also those with more than 10 diverticula had the highest risk of HEM (OR=3.33). Indeed, DIV was deemed by the authors even more important than diet or constipation for internal HEM development.

Epidemiological research has shown relevant differences between sexes in clinical manifestations, severity, and progression of cardiovascular and metabolic disorders. To date, the mechanisms underlying these differences remain unknown. Given the rising incidence of such diseases, gender-specific research on established and emerging risk factors, such as dysfunction of glycaemic and/or lipid metabolism, of sex hormones and of gut microbiome, is of paramount importance. The relationships between sex hormones, gut microbiome and host glycaemic and/or lipid metabolism is largely unknown even in the homeostasis status. Yet this knowledge-gap would be pivotal to pinpoint to key mechanisms that are likely to be disrupted in disease context. Here we present the Women4Health (W4H) cohort, a unique cohort comprising up to 300 healthy women followed up during a natural menstrual cycle, set up with the primary goal to investigate the combined role of sex hormones and gut microbiota variations in regulating host lipid and glucose metabolism during homeostasis, using a multi-omics strategy. Additionally, the W4H cohort will take into consideration another ecosystem that is unique to women, the vaginal microbiome, investigating its interaction with gut microbiome and exploring – for the first time - its role in cardiometabolic disorders. The W4H cohort study lays a foundation for improving current knowledge of women-specific mechanisms in cardiometabolic regulation. It aspires to transform insights on host-microbiota interactions into prevention and therapeutic approaches for personalised health care.

Aims:Epidemiological research has shown relevant differences between sexes in clinical manifestations, severity, and progression of cardiovascular and metabolic disorders. To date, the mechanisms underlying these differences remain unknown. Given the rising incidence of such diseases, gender-specific research on established and emerging risk factors, such as dysfunction of glycaemic and/or lipid metabolism, of sex hormones and of gut microbiome, is of paramount importance. The relationships between sex hormones, gut microbiome, and host glycaemic and/or lipid metabolism are largely unknown even in the homoeostasis status. Yet this knowledge gap would be pivotal to pinpoint to key mechanisms that are likely to be disrupted in disease context.Methods and results:Here we present the Women4Health (W4H) cohort, a unique cohort comprising up to 300 healthy women followed up during a natural menstrual cycle, set up with the primary goal to investigate the combined role of sex hormones and gut microbiota variations in regulating host lipid and glucose metabolism during homoeostasis, using a multi-omics strategy. Additionally, the W4H cohort will take into consideration another ecosystem that is unique to women, the vaginal microbiome, investigating its interaction with gut microbiome and exploring-for the first time-its role in cardiometabolic disorders.Conclusion:The W4H cohort study lays a foundation for improving current knowledge of women-specific mechanisms in cardiometabolic regulation. It aspires to transform insights on host-microbiota interactions into prevention and therapeutic approaches for personalized health care.

Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established 1 – 6 , little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N -acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO -associated species can also utilize GalNAc, particularly Collinsella aerofaciens . The GalNAc utilization genes are also associated with the host’s cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host–microbiome relationship.

Genetic susceptibility to metabolic associated fatty liver disease (MAFLD) is complex and poorly characterized. Accurate characterization of the genetic background of hepatic fat content would provide insights into disease etiology and causality of risk factors. We performed genome-wide association study (GWAS) on two noninvasive definitions of hepatic fat content: magnetic resonance imaging proton density fat fraction (MRI-PDFF) in 16,050 participants and fatty liver index (FLI) in 388,701 participants from the United Kingdom (UK) Biobank (UKBB). Heritability, genetic overlap, and similarity between hepatic fat content phenotypes were analyzed, and replicated in 10,398 participants from the University Medical Center Groningen (UMCG) Genetics Lifelines Initiative (UGLI). Meta-analysis of GWASs of MRI-PDFF in UKBB revealed five statistically significant loci, including two novel genomic loci harboring CREB3L1 (rs72910057-T, P = 5.40E-09) and GCM1 (rs1491489378-T, P = 3.16E-09), respectively, as well as three previously reported loci: PNPLA3, TM6SF2, and APOE. GWAS of FLI in UKBB identified 196 genome-wide significant loci, of which 49 were replicated in UGLI, with top signals in ZPR1 (P = 3.35E-13) and FTO (P = 2.11E-09). Statistically significant genetic correlation (rg) between MRI-PDFF (UKBB) and FLI (UGLI) GWAS results was found (rg = 0.5276, P = 1.45E-03). Novel MRI-PDFF genetic signals (CREB3L1 and GCM1) were replicated in the FLI GWAS. We identified two novel genes for MRI-PDFF and 49 replicable loci for FLI. Despite a difference in hepatic fat content assessment between MRI-PDFF and FLI, a substantial similar genetic architecture was found. FLI is identified as an easy and reliable approach to study hepatic fat content at the population level.